Improving Tumor Suppression Effects of Cisplatin Utilizing a HPV Derived Peptide for Head and Neck Cancers

Description:

Inventors found that human papillomavirus (HPV) activates a specific protein called E2F5 to improve cell death in HPV(+) head and neck squamous cell carcinoma (HNSCC) cells and tumors in culture and in animals. Using molecular, pharmacologic and genetic tools, the inventors have shown that HPV early protein 7 (E7) enhances ceramide-mediated lethal mitophagy in response to chemotherapy-induced cellular stress in HPV-positive HNSCC cells by selectively targeting retinoblastoma protein (RB). Inhibition of RB by HPV-E7 relieves E2F5, which then associates with DRP1, providing a scaffolding platform for Drp1 activation and mitochondrial translocation, leading to mitochondrial fission and increased lethal mitophagy. Ectopic expression of a constitutively active mutant RB, which is not inhibited by HPV-E7, attenuated ceramide-dependent mitophagy and cell death in HPV(+) HNSCC cells. Molecular modeling studies revealed a specific amino acid sequence of E2F5 that is required for Drp1 association and activation. Moreover, mutation of E2F5 to prevent Drp1 binding/activation inhibited mitophagy in HPV+ cells. Activation of Drp1 with E2F5-mimetic peptide for inducing Drp1 mitochondrial localization, enhanced ceramide-mediated mitophagy, and led to tumor suppression in HPV-negative HNSCC-derived xenograft tumors in response to cisplatin in SCID mice (Figure H).

 

 

Overview: HPV infection is linked to improved survival in response to chemo-radiotherapy for patients with oropharynx HNSCC. However, mechanisms involved in increased HNSCC cell death by HPV signaling in response to therapy are largely unknown. The inventors have demonstrated that inhibition of RB by the HPV-E7 oncoprotein relieves E2F5, which then associates with Drp1 as a scaffolding protein, resulting in Drp1-mediated mitochondrial fission, induction of ceramide-dependent lethal mitophagy, and tumor suppression. The discovery of the mechanism by which HPV-E7 induces stress-mediated cell death, at least in part, by ceramide-dependent lethal mitophagy, has important implications for identification of novel targets and therapeutic strategies to improve treatments in various cancers, such as cervical and HNSCC, without pathogenic HPV infection. 

 

Applications: Therapeutic agent to improve conventional chemotherapy for the treatment of patients with HNSCC and cervical cancers, mimicking HPV-E7 signaling to enhance cancer cell death.

Advantages:  Improved treatment of various cancers, such as HNSCC, without pathogenic HPV infection

Key Words: cancer, oncology, HPV, HPV-E7, Human Papilloma Virus, head and neck squamous cell carcinoma, HNSCC, cisplatin, ceramide, EF25, Drp1, mitochondrial fission, mitophagy, tumor suppression

 

Publications: Thomas, Raquela J., et al. “HPV/E7 induces chemotherapy-mediated tumor suppression by ceramide-dependent mitophagy” EMBO Molecular Medicine (2017).

 

Inventors: Besim Ogretmen, Raquela Thomas, Natalia Oleinik

Patent Status:        Provisional Patent Filed 10/31/2016

MUSC-FRD Technology ID: P1707

 

Patent Information:
Category(s):
Therapeutic
For Information, Contact:
Mark Hankins
Director of Licensing
MUSC Foundation for Research Development
hankinsm@musc.edu
Inventors:
Besim Ogretmen
Raquelia Thomas
Natalia Oleinik
Keywords:
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